The novel compound STK405759 is a microtubule-targeting agent with potent and selective cytotoxicity against multiple myeloma in vitro and in vivo

Oncotarget. 2016 Sep 20;7(38):62572-62584. doi: 10.18632/oncotarget.11539.


Despite advances in treatment, multiple myeloma (MM) remains incurable. Here we propose the use of STK405759, a novel microtubule targeting agent (MTA) and member of the furan metotica family for MM therapy.STK405759 inhibited tubulin polymerization in a cell-free system and in myeloma cells. This molecule had potent cytotoxic activity against several MM cell lines and patient-derived MM cells. Moreover, STK405759 demonstrated cytotoxicity against drug-resistant myeloma cells that overexpressed the P-glycoprotein drug-efflux pump. STK405759 was not cytotoxic to peripheral blood mononuclear cells, including activated B and T lymphocytes. This compound caused mitotic arrest and apoptosis of myeloma cells characterized by cleavage of poly (ADP-ribose) polymerase-1 and caspase-8, as well as decreased protein expression of mcl-1. The combination of STK405759 with bortezomib, lenalidomide or dexamethasone had synergistic cytotoxic activity. In in vivo studies, STK405759-treated mice had significantly decreased MM tumor burden and prolonged survival compared to vehicle treated- mice.These results provide a rationale for further evaluation of STK405759 as monotherapy or part of combination therapy for treating patients with MM.

Keywords: AKT; apoptosis; cell cycle; multiple myeloma; tubulin.

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism
  • Animals
  • Antineoplastic Agents / pharmacology*
  • Apoptosis / drug effects
  • Caspase 8 / metabolism
  • Cell Cycle / drug effects
  • Cell Line, Tumor
  • Cell Survival
  • Coculture Techniques
  • Furans / pharmacology*
  • Humans
  • Indoles / pharmacology*
  • Leukocytes, Mononuclear / drug effects
  • Leukocytes, Mononuclear / metabolism
  • Male
  • Mice
  • Mice, SCID
  • Microtubules / drug effects*
  • Multiple Myeloma / drug therapy*
  • Neoplasm Transplantation
  • Poly(ADP-ribose) Polymerases / metabolism


  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • Antineoplastic Agents
  • Furans
  • Indoles
  • STK405759
  • Poly(ADP-ribose) Polymerases
  • CASP8 protein, human
  • Caspase 8